9 alpha-hydroxypregnanes and process for production thereof



United States Patent This invention relates to the production of steroids. More particularly, the invention relates to a new method for the production of steroids and to intermediate compounds produced in the synthesis of those steroids.

In particular, the invention relates to the production of steroids represented by the formula:

( C HzY wherein Y represents hydrogen, fluorine, hydroxy or lower alkanoyl, and Z represents hydrogen or u-hydroxy. 0

The compounds of Formula I may be produced from starting materials of the general formula (II) CH2Y/ wherein Y' represents hydrogen, hydroXy or fluorine. 1t has been found that when the compounds of Formula I are ketalized in the 3- and 20-positions, epoxidation of the bisketals preferentially yields the 9u,llu-oxides and these oxides can then be reduced to the 9oc-hYdIOXY ketals of Formula V by means of lithium aluminum hydride in tetrahydrofuran. Hydrolytic removal of the ketal groups yields the 9oL-hydroxy compounds of Formula I.

Thus starting materials such as A -pregnadiene 3,20 dione; A pregnadiene 17a-ol-3,20-dione; A -pregnadiene-17a,21-diol-3,20-dione; or 2l-fluoro- A -pregnadiene-l7a-ol-3,20-dione may be converted to the corresponding 9a-hydroxy compound, i.e. 9a-hydroXy-A -pregnene-3,20-dione; 9a,17u-dihydroxy-A -pregnene-3,20-dione; 9(n21-dihydroxy-A -pregnene-3,20-dione; 9a,17a,21 trihydroxy-A' -pregnene 3,20 dione; or 21- fluoro 9a,17u-dihydroxy-A -pregnene-3,ZO-dione, respectively, by the sequence of steps which constitutes this invention.

In the first step of the synthesis, a compound of 0 "ice Formula II is converted to its cyclic bis-ketal, e.g., bisethylene ketal, of the formula (III) CH Y' by reaction with a ketalizing agent such as ethylene glycol, propylene glycol, etc., in the presence of a strong acid such as p-toluenesulfonic acid.

The bis-ketal is then preferentially converted to the 9a,11oL-0Xid6 of the formula (IV) GHzY' by treatment with an organic per-acid such as perbenzoic acid, perphthalic acid, peracetic acid or the like.

The compound of Formula IV is reduced with lithium aluminum hydride in boiling tetrahydrofuran (or other higher boiling ether, e.g., ethylene glycol dimethyl ether) to the compound of the formula (V) CH Y 3 EXAMPLE 1 9,11-Dehydrpr0gester0ne 3,20-Bisethylene Ketal A solution of 10 g. of 9,1l-dehydroprogesterone and 200 mg. of p-toluenesulfonic acid in a solution of 350 ml. of benzene and 80 ml. of ethylene glycol is heated at reflux with stirring using. a Dean-Stark separator for 18 hours. The cooled solution is neutralized immediately by the addition of saturated sodium bicarbonate solution, the benzene phase washed three times with water, dried over sodium sulfate and evaporated to dryness. The crude residue on crystallization-from acetone yields the bisketal possessing the following properties: M.P. 18018Q;

[M -6.4 (c., .5 8 in chlf.).

Analysis.Calcd. for C H O (400.54): C, 75.96; H, 9.06. Found: C, 75.46; H, 8.92.

EXAMPLE 2 9a,]1a-Oxidoprogester0ne 3,20-Bz'sethylene Ketal To a solution of 9,11-dehydroprogesterone 3,20-bisethylene ketal obtained in Example 1 (2 g.) in 50 ml. of benzene are added at 0 13.5 ml. (1.15 mole/mole of steroid) of a .43 molar solution of monoperphthalic acid in ether. The reaction mixture is kept in the refrigerator for 16 hours, following which it is washed with 80 ml. of a 4% sodium sulfite solution followed by dilute sodium bicarbonate and water. The chloroform-ether solution is then dried over sodium sulfate and the solvents evaporated in vacuo. Crystallization of the residue from acetone gives pure 9a,lla-oxidoprogesterone 3,20-bisethylene ketal possessing the following'properties: M-.P. 2l8220; [(11 +9.5 (c., .43 in chlf.).

Analysis.Calcd. for C H O (416.54): C, 72.08; H, 8.71. Found: C, 71.73; H, 8.92.

When the perphthalic acid is replaced by perbenzoic acid the 9a,11a-oxide is obtained in equivalent yield.

EXAMPLE 3 9a-Hydr0xypr0gester0ne 3,20-Bz'sethylene Ketal A solution of 500 mg. of 9u,1la-oxidoprogesterone 3,20-bisethylene ketal and 1 g. of lithium aluminum hydride in 50 ml. of freshly distilled tetrahydrofuran is refluxed under nitrogen for 22 hours. The reaction mixture is treated with a saturated solution of sodium sulfate with external cooling and the resulting mixture extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude residue (500 mg.) on crystallization from acetone furnishes pure 9oc-hYd1OXYPI'Og6S- terone 3,20-bisethylene ketal possessing the following properties: M.P. 168170; [ch -50.5 (c., .61 in chlf.)

Analysis.Calcd. for C H O (418.55): C, 71.74; H, 9.15. Found: C, 71.59; H, 8.95.

EXAMPLE 4 9a-Hydroxyprogesterone To a solution of 50 mg. of 9a-hydroxyprogesterone 3,20-bisethylene ketal in ml. of methanol is added .34 m1. of 8% sulfuric acid (w./v.) and the resulting solution refluxed on the steam bath for /2 hour. After cooling, sodium bicarbonate solution is added and the methanol evaporated in vacuo. The residual aqueous suspension is extracted with chloroform, the chloroform phase washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. Crystallization of the crude residue from ethyl acetate and a second recrystallization from ethyl acetate gives analytically pure 9u-hydroxyprogesterone which possesses the following properties: M.P.' 186-188"; +186 (c., .57 in chlf.);

A313 242 m,u( e 17,000); A2335 2.94, 5.87, 6.09 and 6.20 1

Analysis.-Calcd. for (3 1-1 0 (330.45): C, 76.33; H, 9.15. Found: C, 76.36; H, 9.08.

EXAMPLE 5 By substituting 9,1l-dehydro-l7a-hydroxyprogesterone for the 9,1l-dehydroprogesterone in Example 1 and following the same sequence of processing as in Examples 2 to 4, 9,1l-dehydro-17a-hydroxyprogesterone 3,20-bisethylene ketal, 9oc,l1oc-OXiClO-l7oc-l1Yd1OXYPI'Og6S't6IOI16 3,20-bisethylene ketal, 91x,17ot-dihydroxyprogesterone 3,20-bisethylene ketal, and 91x,17a-dihydroxyprogesterone are produced, respectively.

EXAMPLE 6 By substituting 9,11-dehydro-l l-deoxycorticosterone for the 9,11-dehydroprogesterone in Example 1 and following the same sequence of processing as in Examples 2 to 4, A -pregnadiene-21-ol-3,20-dione 3,20-bisethylene ketal, 911,11a-oxido-A -pregnene-2l-ol-3,20-diol 3,20- bisethylene ketal, 9a,2l-dihydroxy A -pregnene 3,20-dione 3,20-bisethylene ketal and 901,2l-dihydroxy-A -pregnene 3,20-dione are produced, respectively.

EMMPLE 7 By substituting A -pregnadiene-l7oc,2l-diol-3,20-dione for the 9,11-dehydroprogesterone in Example 1 and following the same sequence of processing as in Exampics 2 to 4, A -pregnadiene-17a,21-diol-3,20-dione 3,20-bisethylene ketal, 901,1la-oxido-A -pregnene-1711,21- diol-3,20-dione 3,20-bisethylene ketal, 9a,l7a,-2'ltrihydroXy-A -pregnene 3,20-dione 3,20-bisethylene ketal and 9a,17a,2l-trihydroxy-h -pregnene 3,20-dione are produced, respectively.

EXAMPLE 8 wherein Y represents a member of the group consisting of hydrogen, fluorine, hydroxy and lower alkanoyl, and Z represents a member of the group consisting of hydrogen and OC-hydI'OXy, which comprises, insequence, ketalizing in the 3- and 20- positions a compound of the formula wherein Y represents a member of the group consistingof hydrogen,.fluorine and hydroxy, and Z repre sents a member of the group consisting of hydrogen and whydroxy,

epoxiding the 3,20-bis ketal formed, reducing the 900,11- oxido product by means of lithium aluminum hydride in tetrahydrofuran and removing the ketal groups by hydrolysis with dilute acid.

2. A process for producing 9a-hydroxyprogesterone which comprises ketalizing 9,11-dehydroprogesterone in the 3- and 20-positions, converting the 3,20-bis ketal of 9,11-dehydroprogesterone thus formed to the 90,11oc-0Xid6 by oxidation with an organic peracid, reducing the oxide with lithium aluminum hydride in tetrahydrofuran and removing the ketal groups by hydrolysis with dilute acid.

3. A compound of the formula wherein Z represents a member of the group consisting of hydrogen and u-hydroxy.

6 4. A compound of the formula (IJHZF 0 1 5 o to J 0 wherein Z represents a member of the group consisting of hydrogen and oc-hydroxy.

5. 21 fluoro A pregnadiene-l7u-ol-3,20-dione- '3,-20-bisethylene ketal.

References Cited in the file of this patent UNITED STATES PATENTS 2,732,383 Bernstein et a1 Ian. 24, 1956 2,838,501 Campbell et al June 10, 1958 2,840,578 Perlman et a1 June 24, 1958 25 2,844,513 Wettstein et a1 July 22, 1958 3,009,935 Cutler NOV. 21, 1961 3,040,065 Schneider et al June 19, 1962 3,072,684 Fried Jan. 8, 1963 OTHER REFERENCES Allen et a1. J.A.C.S. 77, p. 1028-32 (1955). Loewenthal: Tetrahedron, vol. 6, p. 287-91 (1959). 

3. A COMPOUND OF THE FORMULA 